On behalf of the RE-VERSE AD Investigators Reversal of Dabigatran by its Specific Reversal Agent Idarucizumab in Patients with Uncontrolled Bleeding or Requiring Urgent Surgery/Procedures: Final Results of RE-VERSE AD CV Pollack Jr, PA Reilly, J van Ryn, J Eikelboom, S Glund, RA Bernstein, R Dubiel, MV Huisman, EM Hylek, C-W Kam, PW Kamphuisen, J Kreuzer, JH Levy, FW Sellke, G Royle, J Stangier, T Steiner, P Verhamme, B Wang, L Young, JI Weitz On behalf of the RE-VERSE AD Investigators

Idarucizumab specifically reverses the anticoagulant activity of dabigatran Humanized Fab: binds free- and thrombin-bound dabigatran High binding affinity for dabigatran (2pM); is essentially irreversible No known off-target effects; does not reverse heparins or other anticoagulants IV administration, immediate onset of action, short half-life (~45 min) No intrinsic procoagulant or anticoagulant activity Blood 2013;121:3554-62; Circulation 2015;132:2412.-22; Lancet 2016;386:680-890; Thromb Haemost 2017;117:269-76

Multicentre, Prospective, Open-label, Single-arm Phase III Study Dabigatran etexilate treated patients: Group A: Uncontrolled bleeding 5 g idarucizumab (2 x 2.5 g IV) N = 503 Group B: Emergency surgery or procedure 0–15 min Hospital arrival Baseline Between vials Patients treated based only on clinical presentation 173 sites in 39 countries dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time Thromb Haemost 2015;114:198–205; NEJM 2015:373:511-20.

Multicentre, Prospective, Open-label, Single-arm Phase III Study Dabigatran etexilate treated patients: Primary endpoint: Blood sample time points 2 h 4 h 1 h ~20 min Maximum reversal within 4 hrs with dTT and ECT measures Group A: Uncontrolled bleeding 5 g idarucizumab (2 x 2.5 g IV) N = 503 Group B: Emergency surgery or procedure 0–15 min Hospital arrival Baseline Between vials Patients treated based only on clinical presentation 173 sites in 39 countries dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time Thromb Haemost 2015;114:198–205; NEJM 2015:373:511-20.

Multicentre, Prospective, Open-label, Single-arm Phase III Study Dabigatran etexilate treated patients: Primary endpoint: Blood sample time points 2 h 4 h 1 h ~20 min Maximum reversal within 4 hrs with dTT and ECT measures Secondary endpoints: 90 day follow-up 12 h 24 h 30 d Determined locally Hemostasis within 24 hours (non-ICH) Hemostasis during procedure /surgery Group A: Uncontrolled bleeding 5 g idarucizumab (2 x 2.5 g IV) N = 503 Group B: Emergency surgery or procedure 0–15 min Hospital arrival Baseline Between vials Patients treated based only on clinical presentation 173 sites in 39 countries dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time Thromb Haemost 2015;114:198–205; NEJM 2015:373:511-20.

Multicentre, Prospective, Open-label, Single-arm Phase III Study Dabigatran etexilate treated patients: Primary endpoint: Blood sample time points 2 h 4 h 1 h ~20 min Maximum reversal within 4 hrs with dTT and ECT measures Secondary endpoints: 90 day follow-up 12 h 24 h 30 d Determined locally Hemostasis within 24 hours (non-ICH) Hemostasis during procedure /surgery Group A: Uncontrolled bleeding Thrombotic events Restart of anticoagulation Mortality aPTT / TT Drug levels Immunogenicity 5 g idarucizumab (2 x 2.5 g IV) N = 503 Group B: Emergency surgery or procedure 0–15 min Hospital arrival Baseline Between vials Patients treated based only on clinical presentation 173 sites in 39 countries dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time Thromb Haemost 2015;114:198–205; NEJM 2015:373:511-20.

Patient Demographics Characteristic Group A (n=301) Group B (n=202) Total (N=503) Age (y)* 79 (24–96) 77 (21–96) 78 (21–96) Male sex, n (%) 172 (57.1) 102 (50.5) 274 (54.5) Creatinine clearance (mL/min)* 50.8 (6.1–216.9) 56.0 (7.9–198.7) 52.6 (6.1–216.9) Comorbidities, n (%) Congestive Heart Failure 117 (38.9) 65 (32.2) 182 (36.2) Diabetes 95 (31.6) 57 (28.2) 152 (30.2) Coronary Artery Disease 110 (36.5) 68 (33.7) 178 (35.4) Prior Stroke / TIA 73 (24.3) / 27 (9.0) 36 (17.8) / 20 (9.9) 109 (21.7) / 47 (9.3) Dabigatran, n (%) Atrial fibrillation indication 288 (95.7) 190 (94.1) 478 (95.0) Daily dose 150 mg BID 94 (31.2) 151 (30.0) 110 mg BID 185 (61.5) 126 (62.4) 311 (61.8) 75 mg BID 16 (5.3) 8 (4.0) 24 (4.8) Patient-reported time since last dose (hrs)* 14.6 (1.5, 90.4) 18.0 (2.6, 105.8) 15.6 (1.5, 105.8) Elevated dTT at baseline, n (%) 244 (81.1) 152 (75.2) 396 (78.7) Elevated dTT or ECT at baseline, n (%) 276 (91.7) 185 (91.6) 461 (91.7) *Shown as median (range)

Group A: Site of Index Bleed and Severity (n=301) Type of Bleeding* N (%) Intracranial 98 (32.6) Subdural 39 Subarachnoid 26 Intracerebral 53 Gastrointestinal 137 (45.5) Lower 47 Upper 52 Unknown 42 Intramuscular 9 (3.0) Retroperitoneal 10 (3.3) Intra-pericardial 7 (2.3) Intra-articular 5 (1.7) Intraocular 1 (0.3) Other 52 (17.3) Not identified 4 (1.3) Other: epistaxis, hepatic bleed, hematuria, hematomas (such as abdominal wall, subcutaneous at ribs due to trauma), pelvic bleed with multiple pelvic fractures, fingers on right hand cut off by chainsaw. *Bleeding may occur at more than one site. GI, gastrointestinal; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis

Group A: Site of Index Bleed and Severity (n=301) Type of Bleeding* N (%) Intracranial 98 (32.6) Subdural 39 Subarachnoid 26 Intracerebral 53 Gastrointestinal 137 (45.5) Lower 47 Upper 52 Unknown 42 Intramuscular 9 (3.0) Retroperitoneal 10 (3.3) Intra-pericardial 7 (2.3) Intra-articular 5 (1.7) Intraocular 1 (0.3) Other 52 (17.3) Not identified 4 (1.3) Adjudicated ISTH Bleeding Severity: 88% Major and Life-threatening bleeding Other characteristics: 38% Hemodynamic instability 20% Surgical intervention required 26% Trauma-related Other: epistaxis, hepatic bleed, hematuria, hematomas (such as abdominal wall, subcutaneous at ribs due to trauma), pelvic bleed with multiple pelvic fractures, fingers on right hand cut off by chainsaw. *Bleeding may occur at more than one site. GI, gastrointestinal; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis

Group B: Indications for Surgery / Procedures (n=202) (Percent of total shown at end of each bar)

Similar results were obtained with aPTT and TT Primary Results Median maximum reversal within 4 hours measured by dTT and ECT was 100% (95% CI, 100–100%) Similar results were obtained with aPTT and TT dTT normalized* within 4 hours in 241/244 patients (98.8%) in Group A and 150/152 patients (98.7%) in Group B *at or below the upper limit of normal. All data measured in central laboratory, aPTT and TT outcomes were secondary endpoints

Results: Diluted Thrombin Time Assessment of Dabigatran Reversal dTT diluted thrombin time

Results: Dabigatran Reversal Measured as Unbound Dabigatran and aPTT aPTT activated Partial Thromboplastin Time

Group A (n=301): Hemostasis (bleeding cessation) in 24 hours Time to Locally Reported Hemostasis (Bleeding Cessation)* Non-ICH bleeding: 203 patients (assessable in 198) 120 Gastrointestinal (GI) bleeds 78 Non-GI, non-ICH bleeds Evaluated in 134 /198 (67.7%) patients within 24 (+2) hours 25 /198 (12.6%) patients after 24 hours Not evaluated in 39 /198 (19.7%) patients (bleeding location could not be identified) 2.5 (2.2 – 3.9) hours (median, 95% CI) Intracranial hemorrhage (ICH): 98 patients non-interpretable: serial CT scans not mandated by protocol *Based on visualization where possible, or changes in hemoglobin / hematocrit within 24 hrs of idarucizumab administration by the local investigator

Group B: Peri-procedural Hemostasis 197 of 202 (97.5%) patients underwent anticipated surgery/procedures Median time from administration of first vial to procedure was 1.6 hours Adequacy of hemostasis during surgery determined locally 93.4% Normal: as if anticoagulation were absent Abnormal: Mild – oozing, not requiring intervention Moderate – controlled with local intervention Severe – refractory hemorrhage 5.1% 1.5% 0.0% Normal Mildly Abnormal Moderately Abnormal Severely Abnormal

Adjudicated Thrombotic Events Occurring Post-Reversal Events n (%) Group A (n=301) Group B (n=202) Total (n=503) 30 days 14 (4.6) 10 (5.0) 24 (4.8) 90 days 19 (6.3) 15 (7.4) 34 (6.8) At 72 hours post idarucizumab, 22.9% of Group A and 66.8% of Group B had re-started anticoagulation or antiplatelet therapy By 90 days antithrombotic therapy had been re-started in 72.8% of Group A and 90.1% of Group B patients Patients restarted on dabigatran: 28.9% in Group A (median time 16 days) 61.4% in Group B (median time 6 days)

Mortality Within 5 days of idarucizumab treatment, 19 deaths occurred in Group A (6.3%) and 16 deaths occurred in Group B (7.9%) Kaplan–Meier rates at 30 and 90 days: Group A (n=301) Group B (n=202) 30 days Patients at risk, n 254 169 Mortality, % 13.5 12.6 90 days 152 109 18.8 18.9 See table S1 in supplement. This lists all deaths in the 5 day time frame, most are related to the index event. Later deaths (30, 90 days) are more related to other comorbidities or independent events.

Patients Receiving a Second Dose 9 patients* received a second dose (1.8%) 4 in Group A due to re-bleeding ≥ 24 hours post first-dose of idarucizumab 4 in Group B due to post-operative bleeding or requiring a new procedure ≥ 12 hours post first-dose of idarucizumab Group Age/ Gender Dose of Dabigatran (bid) Index event Unbound dabigatran (ng/mL) Creatinine Clearance (mL/min) Approximate Time to Additional dose Reason for additional dose A 60 M 110 Gastrointestinal bleed 955 25.7 48 hr Recurrent bleeding 79 M 325 43.4 36 hr 76 M Hematuria 1360 15.2 24 hr 73 M 329 29.0 B 85 F 75 Intestinal occlusion 51 31.2 5 days New procedure 73 F 150 Ischemic large bowel 1630 34.0 12 hr Postoperative bleeding 82 F Catheter placement for dialysis 271 8.0 6 days 70 M 240 18.6 3 days (dose 2) 8 days (dose 3) Postoperative bleeding and new procedure Suggestions to discuss verbally: spectrum of doses the patients received and wide range of plasma levels, lower creatinine clearance (took this out as a bullet point), and fact that second (or third dose quite a few hours later so there is time to perform assays etc) *one patient received a second dose in error and is not included in this analysis

Discussion Open label cohort study Currently no approved treatment for comparison Inclusive pragmatic study Clinical condition and bedside evaluation drive treatment decision Provides a broad and heterogeneous emergency patient population, including patients requiring urgent surgery and interventions Fixed dose based on anticipated dabigatran loads Overdose or acute renal failure could result in higher dabigatran levels Some patients show re-appearance of low levels of dabigatran at 12-24 hours, usually without clinical consequences May be due to mobilization of dabigatran from tissues or extracellular fluid

Conclusions In a cohort of elderly, multi-morbid patients taking dabigatran etexilate who presented with life-threatening emergencies: 5 g of idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulation Median time to cessation of extracranial bleeding in Group A was 2.5 hours after reversal Median time to invasive procedure after reversal was 1.6 hours Intraoperative hemostasis was “normal” in 93% of Group B patients Prompt re-initiation of antithrombotic therapy post-procedure was safe No safety concerns identified to date

Thank you to all the investigators involved and to the patients in this study